Genetic and functional studies have identified the APOE*4 allele as a strong susceptibility marker for both early- and late-onset Alzheimer's disease (AD). However, the observation that the APOE*4 allele is neither necessary nor sufficient for the expression of AD suggest the possible involvement of additional genetic factors which, either alone or in conjunction with the APOE*4 allele, increase an individual's risk of developing AD. The overall objective of this study is to evaluate the role of genetic variations in other candidate (susceptibility) genes that may alter the risk of AD in the presence or absence of the APOE*4 allele. The chosen candidate genes are involved either in inflammation and the reaction of neuritic plaque or in the cellular pathology of the disease. The objectives of the study will be achieved by fulfilling the following specific aims: 1) to confirm our preliminary observation that a common genetic variation in the signal peptide of ACT is involved in altering the AD risk associated with the APOE*4 allele, 2) to determine ACT levels in plasma and cerebrospinal fluid (CSF) in controls and AD patients and determine the impact of the ACT signal peptide polymorphism in affecting ACT levels ina the two groups. 3) to estimate the extent of neuritic and diffuse plaque formation among the ACT genotypes, 4) in autopsy confirmed AD cases with the ACT/AA genotype, to sequence the exons and flanking intron-exon boundaries of the ACT gene to determine the location of the putative functional mutation, 5) to evaluate the role of known polymorphisms in the c-FOS CTSG, CTSD, UBC, IL1A, IL1B and IL1RN genes and their joint effects with the APOE and ACT polymorphisms in affecting the risk of AD, and 6) to establish new genetic polymorphisms in the HSPA2 and MAPT genes and evaluate their relationships with AD risk alone as well as in combination with APOE, ACT and other polymorphisms as defined in aim 5. The proposed focused genetic and epidemiological studies will enable us to delineate the role of several candidate genes in further refining and defining the role of genes in determining the risk and natural history of AD.